Inhibition of Resistant Variants of HIV Protease HIV/AIDS is a serious pandemic with over 36 million infected people. Antiviral drug therapy has decreased the mortality, although the number of new infections remains about 2 million per year. However, the genetic diversity and high mutability of HIV pose a critical challenge for continued efficacy of drugs and development of effective vaccines. Hence, there is urgent need for new therapies to overcome the problem of drug-resistance. We are tackling this challenge by studying the important drug target of HIV protease. Clinical resistance arises even for the potent antiviral inhibitor darunavir. Our structural analyses have identified distinct molecular mechanisms for resistance including mutations that: 1) decrease protease interactions with inhibitors; 2) decrease the enzyme stability; or 3) influence the dynamics. In the last project period, our X-ray structures have guided the design of novel inhibitors 10-fold more effective than darunavir against highly resistant proteases. We have developed algorithms to predict resistance from genotype sequences and have identified representative mutants with high level resistance. We propose to identify common mechanism for resistance and apply these insights to design and assess new inhibitors. These multidisciplinary studies leverage the expertise, unique resources and novel approaches developed in the PIs groups together with an established set of collaborators to integrate computational, X-ray crystallographic, biochemical and biophysical techniques with inhibitor design, chemical synthesis, and virology studies. The expected outcomes will be 1) accurate predictions for resistance, 2) discovery of novel and conserved molecular mechanisms for resistance, and 3) new antiviral inhibitors for resistant HIV infections.